We have had a long-standing interest in the etiology of severe insulin resistance. Initially, we identified mutations in the insulin receptor gene and studied a group of patients with autoantibodies against the insulin receptor. More recently, we have concentrated on lipodystrophy syndromes: a group of heterogeneous syndromes characterized by lack of adipose tissue and severe insulin reisitance. In a collaboration with Dr. Abhimanyhu Garg (University of Texas Southwestern). We have reported mutations on the Lamin A/C gene in patients with an autosomal dominant form of familial partial lipodystrophy and also reported a mutation in a form of congenital generalized lipodystrophy on chromosome 9q34. The gene codes for an enzyme that is important in triglyceride synthesis. Our major effort has been in a clinical trial of leptin therapy and lipodystrophy. Leptin levels are low in these patients and leptin replacement therapy results in a reduction in hemoglobin A1C, fasting blood glucose, triglyceride values, a reduction in liver size, and an improvement in liver function. Thus,leptin therapy appears to have a major beneficial effect for metabolic abnormalities seen in these patients. Furthermore, in those patients who have normal reproductive organs, leptin therapy results in a robust increase in gonadotropin secretion following GNRH, and this is associated with the beginning of menses in these otherwise amenorrhic patients. We are continuing our studies on the genetics of lipodystrophy, the natural history of other insulin resistance syndromes and espcecially the follow-up of the clinical effects of leptin on lipodystrophy. More recently, we have initiated a novel research study that tests the efficacy of the adipocyte-derived leptin hormone replacement in ameliorating the metabolic abnormalities in patients with insulin receptor mutations. This study provides a unique opportunity to study the peripheral effects of leptin on the muscle and liver, and preliminary results show a favorable response. While the major focus has been on lipaotrophy syndromes, we are continuing our efforts to understand the natural history of other severe insulin resistant states.